The present invention provides a class of compounds, certain 2-substituted carbonyl compounds (2-substituted aldehydes, ketones and carboxylic acid esters), that are capable of killing and/or inactivating pathogens. Members of this class of compounds disinfect biological fluids containing clinically significant biological materials such as proteins and the like without substantial deleterious effect on those materials. It is further contemplated that the disinfecting agents and formulations of the present invention might be used to treat infected multi-cellular organisms, including mammals.
Previously it has been suggested to disinfect air, water, and other materials by bringing the material in contact with various forms of iodine. It has been reported that various biological materials can be disinfected by contacting those materials with iodine-loaded support matrices, such as polyvinyl pyrrolidone. That kind of disinfection has been carried out both as a therapeutic treatment regimen, for instance disinfection of wounds, and for disinfecting various solutions, in particular aqueous solutions such as drinking water, protein solutions, etc. See, e.g., U.S. Pat Nos. 3,817,816; 3,817,860; 4,010,259; 4,190,529; 4,420,590; 4,594,392; 5,639,452; WO 9516511; WO 9748422; WO 9748482; and Hatch G. L., Ind. Eng. Chem. Prod. Res. Dev. 20(2) (1981) 382-5.
Recently, it was discovered that a particularly advantageous effect could be achieved with a solution comprising an effluent taken off an iodinated ion exchange matrix material. The effluent mixture had several surprising advantages: it inactivated a wide range of potent and hardy pathogens without substantial deleterious effect on clinically significant substances such as proteins. Thus, for example, the effluent mixture provided an effective means for disinfecting blood and blood-derived products; thereby affording a greater level of safety in the use of those essential materials. See U.S. patent application Ser. No. 09/159,460.
One of the drawbacks of iodine-loaded support matrices is that they are cumbersome to manufacture, and present uncertainty in application. For example, many proteins, particularly acidic proteins such as Factor IX and albumin, bind to the iodine-loaded matrices. Such protein binding impairs the efficiency and effectiveness of the process. Likewise, protein binding can result in molecular modification of the protein, thereby affecting its biological activity.
Another drawback is that many iodinated matrices release iodide ions and certain oxidizing forms of iodine. Exposure of labile proteins and other clinically significant biological materials to such potent oxidizers must be limited; and so the oxidizing substances must ultimately be removed from the disinfecting mixture. Thus, biological fluids treated with such matrices must be subjected to a laborious and expensive capture step during or shortly after treatment to remove the more noxious forms of iodine.
Moreover, since the actual active agent in the effluent mixtures was not known, those systems presented uncertainties in determining the presence, concentration, efficacy, and stability of the anti-pathogenic agent in any given mixture; and further presented complications in effectively separating the anti-pathogenic agent from otherwise noxious forms of iodine.
Various species of iodine have been suggested as the active agent(s) in those systems. For example, it has been suggested that an active anti-pathogenic agent might be iodine or iodide, per se (I2, Ixe2x88x92, or I3xe2x88x92); or other forms of iodine that form in aqueous media (e.g., HOI, OIxe2x88x92). See, e.g., Hatch G. L., Ind. Eng. Chem. Prod. Res. Dev. 20(2) (1981) 382-5. However, none of those species has been shown to possess the unique features of, for example, the effluent of iodinated ion exchange media. Moreover, nothing in the art has established that those unique features are, in fact, attributable to a singular active agent or class of active agents.
Certain haloacetaldehydes have been synthesized and identified as having some potential clinical significance. For example, trichloroacetaldehyde, both as such and in proforms, has been reported to have medicinal use in liniments and as a sedative/hypnotic or anesthetic. Windholtz et al., THE MERCK Index, 10th edition, p. 288 (Merck and Co., Rahway, N.J., USA (1983)); and Pharmaceutical Substancesxe2x80x94Syntheses, Patents, Applications, pp 392-93 (Kleeman et al. eds., 3rd edition, Thieme Stuttgart, New York (1999)). Trichloroacetaldehyde has also been used in pediatric medicine and dentistry (e.g., Smith, Science, p. 359 (Oct. 19, 1990); Drug Information, p. 937 (McEvoy, ed., American Hospital Formulary Service, American Society of Hospital Pharmacists, Bethesda, Md., USA, (1985)). Chloroacetaldehyde, a metabolite of vinyl chloride, has been implicated as a potential carcinogen and mutagen. See, e.g., Matsuda, T. et al, Carcinogenesis, 10, pp 2389-94 (Oct. 16, 1995); and Jacobsen J. S. et al., Genetics, 121 (2), pp 213-22 (February 1989). However, such materials have not heretofore been shown to be useful in disinfecting various kinds of material.
There is a need for improved compositions and formulations for disinfecting biological fluids and systems. For example, it would be profoundly advantageous to identify, isolate, and synthesize or otherwise more conveniently manufacture one or more discrete chemical agents that mimic the disinfectant capabilities of the effluent mixtures from iodinated ion exchange matrixes. Such advances will enable detection and quantitation of the active agent, which, in turn, will facilitate the preparation of dose-response curves, and efficacy and toxicity studies. The identification of the active agent will further improve the utility of such agents, and thereby improve public health. That is, the identification and further study of those active anti-pathogenic agents will facilitate more reliable and predictable disinfection of biological fluids, such as blood and blood products, and will thereby enhance the safety of clinically significant products and procedures employing those agents.
The present invention presents a class of 2-substituted carbonyl compounds that have pathogen inactivating capabilities. The compounds of the present invention can be formulated into storage stable compositions that are useful for, among other things, disinfecting biological fluids and other materials of biological or non-biological origin. The present invention further affords methods for disinfecting materials, including biological fluids and the like, without concomitant deleterious destruction of labile proteins or other biological materials of clinical significance.
A particular advantage of the compounds of the present invention is that these compounds can be formulated into well-defined compositions comprising a single well-defined active agent. Those compositions retain pathogen inactivating potential, and can be used in the presence of biological materials and clinically significant constituents. The compositions of the present invention can be conveniently manufactured and analyzed for, e.g., concentration, anti-pathogenic potency, efficacy, and storage stability. Thus, the compositions can be effectively standardized, and reliably compounded, packaged, and stored for subsequent use. By resort to a single-agent composition it also more likely that the use of these compounds will result in fewer deleterious reactions or by-products.
It is contemplated that the compounds of the present invention will be useful not only in disinfecting biological fluids and other biological material in vitro, but also as an in vivo or ex vivo therapeutic for treating or preventing infection in animals, including humans.
As used herein, and unless stated otherwise, the term xe2x80x9cpathogenxe2x80x9d includes viruses, bacteria, fungi, prions, prion related proteins, and other micro-organisms capable of exerting pathogenic effects in multi-cellular organisms. Thus, the use of the term xe2x80x9cpathogenxe2x80x9d contemplates micro-organisms capable of causing disease in mammals, including humans.
The term xe2x80x9cpathogen-inactivating-effective amountxe2x80x9d of an active agent for a pathogen present in a material means sufficient quantity or concentration as to reduce or maintain the level of pathogen in the material. The reduction is preferably to a non-pathogenic level. See also below.
The term xe2x80x9cblood productsxe2x80x9d includes blood fractions and blood extracts such as plasma and blood derived products such as clotting factors, red cells, platelets, white cells, immunoglobulins, serum albumin and the like.
The term xe2x80x9cbiological fluidxe2x80x9d refers to liquid mixtures containing one or more bioorganic compounds, e.g. proteins, carbohydrates, nucleic acids, lipids, hormones, amino acids etc, and/or one or more clinically significant constituents and/or pharmacologically active components. Bioorganic compounds may be of clinical significance and/or have pharmacological activity. A biological fluid might be a solution, liquid mixture, suspension, or a paste. The term further includes whole fluids (such as blood), as well as fractions, extracts, dialyzates, effluents, and other products of chemical, chromatographic, etc. separations. Thus, the term includes blood, blood fractions, blood extracts, blood plasma, protoplasm, milk, urine, semen, saliva, plant extracts, reaction products derived from vaccine production, cell culture supernatants, and other fluids, of either natural or synthetic origin (e.g., recombinant or transgenic); and various isolates, effluents, and extracts taken therefrom.
The term xe2x80x9cmaterials of clinical significancexe2x80x9d or xe2x80x9cclinically significant constituentsxe2x80x9d refers to desired components, for instance bioorganic compounds and/or salts that are physiological active and/or physiologically acceptable, or materials having clinical or therapeutic activity, either as an agonist or antagonist, that may be present in biological fluids or derived of biological origin, whether natural, transgenic, or recombinant. The term includes pharmacologically active or useful proteins, polysaccharides, lipids, nucleic acids, and hormones.
The term xe2x80x9cproteinxe2x80x9d refers to compounds comprised of one or more chains of amino acids connected by peptide linkages; and includes compounds containing any such fundamental peptide structure, e.g., oligopeptides and polypeptides, as well as oligo- and polypeptides covalently linked to matrices or polymeric supports. Protein mixtures include: liquid mixtures, pastes, or solutions of: albumin of various kinds (e.g. serum albumin); proteases; protease inhibitors; clotting factors such as fibrinogen, Factor VII, Factor VIII, and Factor IX; protein C; immunoglobulins, particularly IgG, including hyperimmune Igs; monoclonal antibodies, and growth factors. Other proteins of interest are lactoperoxidase and lactoferrin.
The term xe2x80x9cdisinfectxe2x80x9d means to remove, kill, destroy, or otherwise render non-pathogenic a pathogenic component. Likewise, the term xe2x80x9cpathogen inactivationxe2x80x9d or xe2x80x9cpathogen inactivatingxe2x80x9d means killing, destroying, or otherwise rendering non-pathogenic a pathogenic component of an otherwise pathogenic species. To render non-pathogenic means to impair a vital function of the pathogen or merely reduce it in number or concentration such that a host""s immune system can otherwise dispose of it. Examples of pathogenic components are virus, bacterium, fungus, other pathogenic microorganisms, or other pathogenic species such as the infective agent for transmissible spongiform encephalopathies, e.g., prion, prion-related proteins (xe2x80x9cPRPxe2x80x9d), and the like.
The term xe2x80x9cbiological systemxe2x80x9d means multi-cellular organisms, and includes mammals.
As used herein, xe2x80x9cmaterialsxe2x80x9d to be disinfected include inorganic and organic material, such as biological fluids, bioorganic molecules, clinically significant constituents, surfaces contaminated or suspected of being contaminated by pathogens, water, air, etc. In a broad sense the term also includes biological systems, for instance cell cultures and multi-cellular organisms such as animals potentially infected with the various pathogens or which are at risk of becoming infected with pathogens.
Unless stated otherwise, all quantities or concentrations expressed as a percentage (%) are percent by weight.